Extracorporeal ambulator assist lung

ABSTRACT

A extracorporeal system for lung assist includes a housing, a blood flow inlet in fluid connection with the housing; a blood flow outlet in fluid connection with the housing; a plurality of hollow gas permeable fibers adapted to permit diffusion of gas between blood and an interior of the hollow gas permeable fibers, the plurality of hollow gas permeable fibers being positioned between the blood flow inlet and the blood flow outlet such that blood flows around the plurality of hollow gas permeable fibers when flowing from the blood flow inlet to the blood flow outlet; a gas inlet in fluid connection with the housing and in fluid connection with inlets of the plurality of hollow gas permeable fibers; a gas outlet in fluid connection with the housing and in fluid connection with outlets of the plurality of hollow gas permeable fibers; and at least one moving element to create velocity fields in blood flow contacting the plurality of hollow gas permeable fibers. The plurality of hollow gas permeable fibers may extend generally perpendicular to the direction of bulk flow of blood through the housing.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase filing of PCT International PatentApplication No. PCT/US2013/172286, filed Nov. 27, 2013, which claimsbenefit of U.S. Provisional Patent Application Ser. No. 61/730,581,filed Nov. 28, 2012, the disclosures of which are incorporated herein byreference.

BACKGROUND

The following information is provided to assist the reader inunderstanding technologies disclosed below and the environment in whichsuch technologies may typically be used. The terms used herein are notintended to be limited to any particular narrow interpretation unlessclearly stated otherwise in this document. References set forth hereinmay facilitate understanding of the technologies or the backgroundthereof. The disclosure of all references cited herein are incorporatedby reference.

Acute and chronic diseases of the lung remain major healthcare problems.The American Lung Association reports that nearly 350,000 Americans dieeach year of some form of lung disease. Lung disease is the number threekiller of Americans and is responsible for one in seven deaths. Acutelung failure and adult respiratory distress syndrome (ARDS) areprevalent forms of lung disease. ARDS afflicts about 150,000 Americanseach year. The associated mortality of ARDS remains between 40 and 60%despite improvements in critical care medicine. Most lung disease,however, is chronic. Emphysema and chronic bronchitis, two forms ofchronic obstructive pulmonary disease (COPD), afflict over 14 millionAmericans annually. Chronic lung disease is now the 3rd leading cause ofdeath in America, claiming the lives of over 400,000 annually andcarrying a cost of $154 billion. As chronic lung disease reaches endstage, lung transplantation becomes the only choice for effectivetreatment. Lung transplantation has had a steady rise over the last 10years and ˜3300 lung transplants are performed annually worldwide. Theaverage time on the waiting list varies from 6 to 12 months depending onthe patient's condition and institutional expertise, and 10-15% ofpatients die while on the waiting list in the US. A narrow window ofopportunity exists for lung transplant in any patient who is sick enoughto benefit from the operation, but healthy enough to survive months ofwaiting for a donor lung and then the subsequent surgery.

Once they reach a critical condition, mechanical ventilation andextracorporeal membrane oxygenation (ECMO) are the only alternatives forrespiratory support available to bridge acute and chronic respiratorypatients to lung recovery or lung transplantation. Mechanicalventilation (MV) may maintain adequate gas exchange for short termsupport, but in longer term support can lead to ventilator induced lunginjury from barotrauma (high pressure), volutrauma (over-distension),and biotrauma (molecular and cell mediated inflammation), which canfurther worsen the respiratory status of the patient. ECMO is expensiveand complicated, requiring the use of an external pump and blood circuitthat have to be supervised continuously by highly trained technicians.The confinement of the patient in MV and especially ECMO leads to aprogressive deconditioning that is reflected in higher postoperativecomplications and earlier mortality after transplant. Nevertheless, ECMOhas been increasingly considered as the only alternative to bridgepatients to lung transplant or lung recovery after an acutedecompensation from their disease. More recently, with increasingexperience at active transplant centers and improvement in ECMOtechnology, the concept of “ambulatory ECMO” has gained popularity andfacilitates and expedites patient recovery after transplantation.Success in ambulatory ECMO underscores the importance of maintainingpatient mobility. Currently available ambulatory ECMO systems combineexisting blood pumps and bypass oxygenators into an integrated system,but remain bulky and cumbersome and require frequent exchange of theoxygenators for longer term support.

Recent success with paracorporeal left ventricular assist devices (VADs)for heart failure patients has stimulated envisioning an ambulatorypump-lung device that can be a bridge to lung transplant or recovery. Nofully integrated ambulatory pump-lungs are being used clinically,however. Portable or ambulatory systems under development integrate aseparate blood pump and oxygenator under a single controller unit, butremain cumbersome. In such devices, a blood pump is typically connectedby one or more conduits (for example, lengths of tubing) to anoxygenator. While a number of systems have integrated blood pumps, theblood leaving the impeller unit of these devices typically travelsthrough channels before being distributed by manifolds into the hollowfiber bundle compartment.

SUMMARY

In one aspect, an extracorporeal (for example, a paracorporeal) systemfor lung assist includes a housing, a blood flow inlet in fluidconnection with the housing; a blood flow outlet in fluid connectionwith the housing; a plurality of hollow gas permeable fibers adapted topermit diffusion of gas between blood and an interior of the hollow gaspermeable fibers. The plurality of hollow gas permeable fibers arepositioned between the blood flow inlet and the blood flow outlet suchthat blood flows around the plurality of hollow gas permeable fiberswhen flowing from the blood flow inlet to the blood flow outlet. Thesystem further includes a gas inlet in fluid connection with the housingand in fluid connection with inlets of the plurality of hollow gaspermeable fibers; a gas outlet in fluid connection with the housing andin fluid connection with outlets of the plurality of hollow gaspermeable fibers; and at least one moving element to create velocityfields (that is, velocity field associated with the moving element ordisturbed velocity fields) in blood flow contacting the plurality ofhollow gas permeable fibers. The plurality of hollow gas permeablefibers may, for example, extend generally perpendicular to the directionof bulk flow of blood through the housing. Blood may be blocked fromflowing to the gas inlet and the gas outlet.

The at least one moving element may, for example, include a rotatingelement. The rotating element may, for example, be provided with vanesand/or other extending elements (for example, axially extendingelements) to enhance velocity fields created thereby. In a number ofembodiments, the at least one moving element includes a rotatingimpeller adapted to pump blood from the blood flow inlet to the bloodflow outlet. In a number of embodiments, the rotating impeller rotatesin a plane generally parallel (that is, within no more than 5 degrees orwithin no more than 2.5 degrees of parallel) to an orientation of thehollow gas permeable fibers. In a number of embodiments, a surface ofthe rotating impeller is directly adjacent the plurality of hollow gaspermeable fibers or fiber bundle. The surface of the rotating impelleradjacent the plurality of hollow gas permeable fibers may, for example,include vanes and/or other extending elements to enhance velocity fieldscreated thereby. The impeller may, for example, include a disk, a firstplurality of vanes on a first side of the disk and a second set of vanesor extending elements on a second side of the disk. The rotation of theimpeller (or other rotating element) causes active mixing within theplurality of hollow gas permeable fibers. In a number of embodiments,the impeller includes a plurality of magnets in operative connectiontherewith and the system further comprises a magnetic drive system.

A spinning or rotating impeller or other element produces active bloodmixing as a result of the swirling flow from the impeller penetratinginto the fiber bundle. Active mixing refers generally to an increase inmass transfer efficiency of the lung compartment by disturbing thevelocity fields contacting hollow fiber membranes. The increasedexchange efficiency can reduce the required fiber surface area andpriming volume, allowing the lung compartment of the system and overallsystem to be more compact. In a number of embodiments, a first stage(that is, a side of opposite the side adjacent the fiber bundle) of theimpeller imparts centrifugal momentum to the blood that enters from theblood flow inlet (for example, directly to the center of the impeller.The second stage (that is, the side adjacent the fiber bundle)distributes the blood over the fiber bundle and converts the momentumimparted into pressure to drive axial flow through the lung compartment.

In a number of embodiments, the plurality of hollow gas permeable fibersis formed in at least one generally cylindrical bundle. The generallycylindrical bundle may, for example, be formed from a plurality oflayers of fiber fabric (that is, a generally planar array, membrane offabric of hollow gas permeable fibers). Each of the plurality of layersof fiber fabric includes hollow gas permeable fibers oriented ingenerally the same direction. Adjacent layers of fiber fabric may, forexample, be rotated relative to each other such that the orientation ofthe plurality of hollow gas permeable fibers in adjacent layers of fiberfabric are of a different orientation.

In a number of embodiments, a first seal is formed between the generallycylindrical bundle and the housing at a first position, and a secondseal is formed between the generally cylindrical bundle and the housingat a second position, rotated around the circumference of the generallycylindrical bundle from the first position, to form a gas inlet manifoldin fluid connection with the gas inlet on a first side of the first sealand the second seal and a gas outlet manifold in fluid connection withthe gas outlet on a second side of the first seal and the second seal.The first seal and the second seal block fluid connection between thegas inlet manifold and the gas outlet manifold.

The system may, for example, further include a moving/rotating elementpositioned within the housing adjacent to the plurality of hollow gaspermeable fibers on an opposite side thereof of the impeller. Therotating element may, for example, include a second impeller. In systemsincluding a plurality of fiber bundles, one or more moving/rotatingelement may, for example, be placed between adjacent fiber bundles.

The plurality of hollow gas permeable fibers may, for example, includeat least one species of zwitterionic molecule attached to or tethered onsurfaces thereof. The plurality of hollow gas permeable fibers mayinclude heparin attached to or tethered on surfaces thereof.

In a number of embodiments, the system further includes a system tooffset hydrodynamic force. For example, the system to offsethydrodynamic force may include a first magnet in operative connectionwith the impeller which cooperates with a second magnet to create arepellant force therebetween. In embodiments including a magnetic drive,such a system may be used to offset both hydrodynamic force and magneticcoupling force between the plurality of magnets and the magnetic drive.

The system may, for example, be adapted to deliver flows in the range orapproximately 2 to 4 liters per minute. The flow or flow rate may, forexample, be adjustable (for example, by varying the speed of animpeller) to, for example, adjust to varying requirements in lungassist.

The system may, for example, further include a first pivot bearing on afirst side of the moveable element (for example, an impeller) and asecond pivot bearing on a second side of the moveable element.

In a number of embodiments, the moveable element (for example, animpeller) includes one more holes or passages therethrough.

The system may, for example, further include at least a second pluralityof hollow gas permeable fibers (for example, a second, generallycylindrical fiber bundle) spaced from the (first) plurality of hollowgas fibers set forth above. The second plurality of hollow gas permeablefibers is adapted to permit diffusion of gas between blood and aninterior of the second plurality of hollow gas permeable fibers. Thesecond plurality of hollow gas permeable fibers is spaced from theplurality of hollow gas permeable fibers between the blood flow inletand the blood flow outlet such that blood flows around the secondplurality of hollow gas permeable fibers when flowing from the bloodflow inlet to the blood flow outlet. The second plurality of hollow gaspermeable fibers may extend generally perpendicular to the direction ofbulk flow of blood through the housing. The gas inlet is in fluidconnection with inlets of the second plurality of hollow gas permeablefibers. The gas outlet is in fluid connection with outlets of the secondplurality of hollow gas permeable fibers. The system may further includeat least a second moving element (for example, a second impeller) tocreate velocity fields in blood flow contacting the second plurality ofhollow gas permeable fibers positioned between the plurality of hollowgas permeable fibers and the second plurality of hollow gas permeablefibers. One or more additional pluralities of hollow gas permeablefibers may be provided in series. Additional moveable element (forexample, impellers) may be provided between adjacent pluralities ofhollow gas permeable fibers to create velocity fields/active mixing.

In another aspect, a method for extracorporeal (for example,paracorporeal) lung assist includes providing a plurality of hollow gaspermeable fibers within a housing, the plurality of hollow gas permeablefibers being adapted to permit diffusion of gas between blood and aninterior of the hollow gas permeable fibers, the plurality of hollow gaspermeable fibers being positioned between a blood flow inlet and a bloodflow outlet such that blood flows around the plurality of hollow gaspermeable fibers when flowing from the blood flow inlet to the bloodflow outlet; flowing a sweep gas including oxygen through the pluralityof hollow gas permeable fibers; and moving at least one movable elementto create velocity fields (that is, velocity field associated with themoving element or disturbed velocity fields) in blood flow contactingthe plurality of hollow gas permeable fibers. In a number of embodiment,the plurality of hollow gas permeable fibers extend generallyperpendicular to the direction of bulk flow of blood through thehousing. The method may, for example, further include element or actionsas described above.

In a further aspect, an extracorporeal (for example, paracorporeal)system for lung assist include a housing, a blood flow inlet in fluidconnection with the housing, a blood flow outlet in fluid connectionwith the housing, a plurality of hollow gas permeable fibers adapted topermit diffusion of gas between blood and an interior of the hollow gaspermeable fibers, the plurality of hollow gas permeable fibers beingpositioned between the blood flow inlet and the blood flow outlet suchthat blood flows around the plurality of hollow gas permeable fiberswhen flowing from the blood flow inlet to the blood flow outlet, a gasinlet in fluid connection with the housing and in fluid connection withinlets of the plurality of hollow gas permeable fibers, a gas outlet influid connection with the housing and in fluid connection with outletsof the plurality of hollow gas permeable fibers, at least one movingelement to create velocity fields in blood flow contacting the pluralityof hollow gas permeable fibers, a first pivot bearing on a first side ofthe moveable element, and a second pivot bearing on a second side of themoveable element. Blood entering the housing may, for example, flowacross the first pivot bearing and the second pivot bearing to flush asurface of the first pivot bearing and a surface of the second pivotbearing.

The present devices, systems and methods, along with the attributes andattendant advantages thereof, will best be appreciated and understood inview of the following detailed description taken in conjunction with theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates a perspective, exploded view of an embodiment of aparacorporeal ambulatory assist lung system hereof.

FIG. 1B illustrates another perspective, exploded view of the system ofFIG. 1A.

FIG. 1C illustrates another perspective, exploded view of the system ofFIG. 1A.

FIG. 2A illustrates a perspective, assembled view of the system of FIG.1A.

FIG. 2B illustrates another perspective, assembled view of the system ofFIG. 1A including a schematic representation of a magnetic drive system.

FIG. 2C illustrates another perspective, assembled view of the system ofFIG. 1A.

FIG. 3A illustrates a top plan view of the system of FIG. 1A.

FIG. 3B illustrates a cross-sectional view of the system of FIG. 1Aalong section B-B of FIG. 3A.

FIG. 3C illustrates a perspective, exploded view of various layers of anembodiment of a fiber bundle hereof wherein the orientation of thefibers in adjacent layers is rotated with respect to each other (whereinthe fibers within individual layers are oriented in generally the samedirection).

FIG. 3D illustrates a perspective, exploded view of a system hereofincluding a plurality of fiber bundles with a rotating or spinningelement positioned therebetween.

FIG. 3E illustrates a perspective, exploded view of another embodimentof a paracorporeal ambulatory assist lung system hereof.

FIG. 3F illustrates another perspective, exploded view of the system ofFIG. 3E.

FIG. 3G illustrates another perspective, exploded view of the system ofFIG. 3E.

FIG. 3H illustrates a top plan view of the system of FIG. 3E.

FIG. 3I illustrates a cross-sectional view of the system of FIG. 3Ealong section C-C of FIG. 3E.

FIG. 4 illustrates the results of a study of normalized VO₂ as afunction of impeller rotation rate.

FIG. 5 illustrates an experimental setup for studying the systemshereof.

FIG. 6 illustrates pump curves showing the results of a study ofpressure head as a function of flow rate at various rotational speeds.

FIG. 7 illustrates the results of a study of blood gas exchange rate asa function of blood flow rate.

FIG. 8 illustrates the results of a study of plasma free hemoglobin.

FIG. 9 illustrates a simulated velocity field which shows the directpenetration of disturbed flow from the impeller into the fiber bundle ofthe system of FIG. 1A.

FIG. 10 illustrates a comparison of simulated velocity fields with andwithout impeller rotation, showing that the disturbed flow resultingfrom impeller rotation propagates about ⅓ or ½ the distance into thefiber bundle, which is demarcated between the dashed lines of FIG. 10.

FIG. 11 illustrates the results of platelet deposition studies ofaminated siloxane fiber (S-A) modified with zwitterionicphosphorylcholine (S-A-PC) and or zwitterionic sulfobetaine (S-A-SB)macromolecules.

DETAILED DESCRIPTION

It will be readily understood that the components of the embodiments, asgenerally described and illustrated in the figures herein, may bearranged and designed in a wide variety of different configurations inaddition to the described example embodiments. Thus, the following moredetailed description of the example embodiments, as represented in thefigures, is not intended to limit the scope of the embodiments, asclaimed, but is merely representative of example embodiments.

Reference throughout this specification to “one embodiment” or “anembodiment” (or the like) means that a particular feature, structure, orcharacteristic described in connection with the embodiment is includedin at least one embodiment. Thus, the appearance of the phrases “in oneembodiment” or “in an embodiment” or the like in various placesthroughout this specification are not necessarily all referring to thesame embodiment.

Furthermore, described features, structures, or characteristics may becombined in any suitable manner in one or more embodiments. In thefollowing description, numerous specific details are provided to give athorough understanding of embodiments. One skilled in the relevant artwill recognize, however, that the various embodiments can be practicedwithout one or more of the specific details, or with other methods,components, materials, et cetera. In other instances, well knownstructures, materials, or operations are not shown or described indetail to avoid obfuscation.

As used herein and in the appended claims, the singular forms “a,” “an”,and “the” include plural references unless the context clearly dictatesotherwise. Thus, for example, reference to “an impeller” includes aplurality of such impellers and equivalents thereof known to thoseskilled in the art, and so forth, and reference to “the impeller” is areference to one or more such impellers and equivalents thereof known tothose skilled in the art, and so forth. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range. Unlessotherwise indicated herein, each separate value and intermediate rangesare incorporated into the specification as if individually recitedherein. All methods described herein can be performed in any suitableorder unless otherwise indicated herein otherwise clearlycontraindicated by the text.

In a number of embodiments, extracorporeal/paracorporeal ambulatoryassist lung system hereof provide advantages in gas transfer efficiencyand biocompatibility. The systems hereof may, for example, be designedfor either central and/or peripheral cannulation and respiratory supportof, for example, 1-3 months duration before device change-out may berequired. Systems hereof are, for example, amenable to patientssuffering from severe acute respiratory failure (ARDS) to chronicpatients suffering from COPD or severe pulmonary hypertension (PH).Paracorporeal device or systems are extracorporeal devices generallylocated immediately adjacent to the body during use. In other words,paracorporeal devices or systems are “wearable” or ambulatory devices orsystems. The systems hereof are well suited for paracorporeal/ambulatoryuse as well as use as generally stationary extracorporeal systems.

The system hereof are less cumbersome than ambulatory ECMO systemscurrently under development while providing for increased ambulatoryrespiratory assist. In a number of embodiments, systems hereof provide ahighly integrated blood pump and lung, in which a pump mechanism such asan impeller spins adjacent to a plurality of hollow gas permeable fibers(sometimes referred to herein as a fiber bundle). Systems hereof may,for example, be designed to be worn in a holster or vestparacorporeally. Directly integrated an impeller or othermoving/rotating element adjacent to the fiber bundle enables impellerrotation to enhance gas exchange. In a number of embodiments, theimpeller of the system hereof is magnetically driven, but does notrequire magnetic levitation, resulting in a lighter, less complex, andless expensive system.

In a number of embodiments of system 10 hereof as illustrated in FIGS.1A through 3C, system 10 includes a housing 20 including a rotatingelement such as a rotating impeller 100 therein, which is, for example,positioned directly adjacent (for example, subjacent in the normalorientation of operation as illustrated in FIG. 3 without interveningflow altering elements) to fiber bundle 200. Housing 20 is formed inmultiple sections (three sections in the illustrated embodiment)including a first end section 30, an intermediate section 40 and asecond end section 50. A blood flow inlet 32 is formed in connectionwith first end section 30, and a blood flow outlet 52 is formed inconnection with second end section 50. Intermediate section 40 includesa gas flow inlet 42 and a gas flow outlet 44.

As, for example, illustrated in FIG. 3B, first end section 30,intermediate section 40 and second end section 50 are connected to formintegral housing 20. In the illustrated embodiment, impeller 100 hasgenerally the same diameter as fiber bundle 200 and is positioneddirectly adjacent fiber bundle 200. In a number of embodiments, thereis, for example, no intervening extending conduit (for example, tubing,channels etc.) through which blood must flow from impeller 100 (or othermoving or rotating element) to reach fiber bundle 200 or other flowrestrictions or obstructions which would cause the viscosity of thefluid to significantly dampen the flow velocity fields created byimpeller 100 or another rotating member. This arrangement produces“active blood mixing” wherein a disturbed flow field generated byrotating impeller 100 penetrates into fiber bundle 200, creating locallyincreased flow velocities. In general, “active mixing” refers toincreasing the mass transfer efficiency of the lung compartment bydisturbing the velocity fields contacting hollow fiber membranesthereof. Such active mixing reduces diffusional boundary layers at thefiber surfaces and results in increased gas exchange.

In that regard, a spinning impeller/surface creates velocitydisturbances, V_(d), in the blood flow path that scale as V_(d)˜2πfD/2,where f is the impeller rotational frequency and D is the impellerdiameter. These velocity disturbances are in addition to and can be10-1000 times greater than the average velocity V_(avg) of blood flowthrough the hollow fiber bundle and are responsible for “active mixing”that enhances gas exchange. The placement of the fiber bundle, forexample, directly adjacent to the spinning impeller/surface allows thedisturbances to be convected into the fiber bundle and produce theactive mixing. In a number of embodiments, systems hereof do not includechannels, pathways, or any other flow directing structures between theimpeller and fiber bundle that would dampen the impeller generatedvelocity disturbances. If L is the distance from the impeller to thefiber bundle and d is the characteristic minimum transverse dimension(i.e. perpendicular to the direction of net flow) of channels, pathways,or other flow directing structures between the impeller and fiberbundle, then the velocity disturbances will be convected to the fiberbundle only if the transit time from the impeller to the fiber bundle ismuch less than the time for transverse diffusion of momentum across thechannels, pathways etc. In a number of embodiments,

$\frac{L}{\overset{\_}{V}}{\operatorname{<<}\frac{d^{2}}{v}}$where V is the mean blood flow velocity towards the fiber bundle in thechannels, pathways, or flow directing structures and v is the kinematicvelocity of blood. The open space between the impeller and fiber bundle(large d) and the placement of the impeller adjacent to the fiber bundle(small L) in the systems hereof maximizes the propagation of theimpeller-generated flow disturbances to the fiber bundle. In a number ofembodiments, the surface of the impeller or other moving/rotatingelement adjacent the fiber bundle is no more than 1 cm from the fiberbundle, no more than 2 mm from the fiber bundle or no more than 1 mmfrom the fiber bundle.

FIG. 3E through 3I illustrate another embodiment of a system 10 a whichis very similar in construction and operation to system 10. In system 10a, components are numbered similarly to like components of system 10with the addition of the designation “a” thereto. During operation, thenegative pressure generated in the system inlet region (that is, thespace between impeller 100 a and the inner wall of section 30 a ofhousing 20 a) results in a force applied on impeller 100 a in thedirection of section 30 a of housing 20 a. This hydrodynamic force, inaddition to the force of ten coupling magnets 150 a, can wear thebearing material (in the housing section 30 a) and lead to pump failureover time. System 10 a include a system to offset the combinedhydrodynamic and coupling magnet forces. In the illustrated embodiment,a repelling magnet 180 a is seated in a seating 128 a of impeller 100 aand (in cooperation with another magnet 190 a (see FIG. 3I) which may beexternal to housing 120 a) is operable to apply force offset thecombined hydrodynamic and coupling magnet forces, thereby minimizing theaxial forces applied to the bearings, and improving overall systemdurability.

FIG. 4 illustrates the effect of active mixing in system 10. Weperformed a standard gas exchange characterization of an embodiment ofsystem 10 in blood using established testing standards. In severalstudies, the blood flowrate through system was a constant 3.3 LPM, whichwas set via a BIOMEDICUS® pump available from Medtronic of Minneapolis,Minn. in the test setup. The rotating speed of impeller 100 was variedfrom 0 (no pumping) to 2500 RPM (all pumping being performed by impeller100). At a constant blood flowrate flowing through system 10, therotation of impeller 100 increased gas exchange by 45% over the range ofstudied impeller rotating speeds (as compared to the case wherein thereis no rotation). In systems in which an impeller is isolated from thefiber bundle via on or more interconnecting conduits/tubes impellerrotation will have no effect on gas exchange at a set constant bloodflowrate through such systems. Active mixing allows for meeting gasexchange design requirements with less fiber surface area, leadingpotentially to a more compact system.

Even with active mixing, the fiber surface area of system 10 may, forexample, be at least ˜½ m² in a number of embodiments. Fiber bundle 200may, for example, include thromboresistant fibers formed of a thinsiloxane layer to prevent plasma wetting with a covalently attachedheparin coating to decrease thrombogenicity. Suitable siloxane-heparinfibers have been developed by Alung Technologies of Pittsburgh, Pa.using the CELGARD® X-240 polypropylene (PP) fiber available from CelgardLLC of Charlotte, N.C. OXYPLUS® polymethylpentene (PMP) hollow fiber orcapillary fabrics or membranes available from Membrana GmbH ofWuppertal, Germany may also, for example, be used.

PP fibers used in studies hereof had an outer diameter or OD of 300micron and an inner diameter or ID of 240 micron. The PMP fibers had anOD of 380 micron and an ID of 200 micron. These fibers were manufacturedas arrays, membranes or fabrics of hollow fibers, wherein a plurality offibers are fabricates as an integral, generally planar array havinggenerally the same fiber orientation. In forming fiber bundle 200, sucharrays, membranes or fabrics are cut into sheets that were placed one ontop of the other in stack of multiple layers (62 layers in the studiedembodiments of fiber bundle 200) such that the overall surface area forgas exchange was maintained at 0.85 m². The porosity of fiber bundle wasmaintained at 0.6. Upon formation, fiber bundle 200 had a diameter of3.85 inches (0.0978 meters) and a height of 0.88 inches (0.0224 meters).The bundle diameter was such that it closely matched the impellerdiameter (3.85 inches or 0.0978 meters).

As described above, the fibers used in the studies of system 10 wereprovided in array, fabric or membrane form. Other approaches toimproving thromboresistance include the use of zwitterionic molecularspecies attached (for example, covalently) to the surface of the fiberswithout significantly affecting gas transport across the fiber surface.Furthermore, blood flow paths and patterns in system 10 may be optimizedusing for example computational fluid dynamics or CFD for improvedhemocompatibility. The ultimate anticoagulation requirements for system10 may also be further reduced because blood exiting system 10 flowsthrough the patient's lungs, which can continue to act as a filter ofsmall emboli.

As described above, blood enters system 10 through blood flow inlet orinlet port 32 and is pumped by radial impeller 100. In a number ofstudied embodiments, impellers 200 was supported by two pivot bearings105 (for example, sapphire or ceramic pivot bearings) mounted intohousing 20 and aligned with the central axis of radial impeller 100. Asknown in the bearing arts, pivot bearing 105 may for example, include arounded end that rotatable relative to a bearing cup 106 (for example,similar to a ball and socket joint) as, for example, illustrated in FIG.3B. Synthetic (ceramic) pivot bearings suitable for user herein are, forexample, available from Swiss Jewel of Philadelphia. Bearing cups 106were formed from ultrahigh molecular weights polyethylene and areavailable from Modern Plastics of Shelton, Conn. The use of pivotbearings 105 eliminate the need for seals and bearings. The pivotbearing maintain impeller 100 axially and radially aligned within system10. Also, secondary saline infusion used in some systems to beep bloodfrom contacting friction/heat generating components are not required.Fresh blood enters system 10 and flows across pivot bearings 105,continually flushing the area with fresh fluid.

Magnetically suspended or levitated impellers without bearings may, forexample, be used to further increase longevity. However, system 10, in anumber of embodiments, may require periodic change-out (for example,every 1-3 months) of system 10 as a result of fouling in the lungcompartment. A simpler and less complex approach of magnetic coupling ofimpeller 100, but not magnetic levitation, was chosen in a number ofembodiments. In the illustrated embodiment, magnets 150, which areseated in seatings 122 (see FIG. 1B), on rotating impeller 100 couplemagnetically to rotating magnets on an external motor driver 300(illustrated schematically in FIG. 2B) to maintain a hermetic seal. In anumber of embodiments, impeller 100 was a two-stage impeller. The firststage of impeller 100 (on a first or blood-inlet side 110 of impeller100) includes a first plurality of impeller vanes 114 and impartscentrifugal momentum to the blood that enters from the blood flow inlet100 to impeller 100. The second stage (on a second or fiber-bundle side120 of impeller 100) includes a second set of vanes 124 to distributethe blood over a surface of fiber bundle 200 and convert the momentumimparted to the blood into pressure to drive axial flow through the“lung compartment” formed by fiber bundle 200.

In the illustrated embodiment, the rotation of impeller 100 wascounterclockwise, and the placement of vanes 114 was concave in thedirection of rotation, such that a pumping action is created uponimpeller rotation. Vanes 114 were designed such that the tip of eachvane 114 formed a 30 degree angle to the tangent at the point where vane114 intersects an outer diameter of that vane. The angle and other vaneproperties can be adjusted to alter the pumping efficiency of impeller114. In a number of embodiment, second stage vanes 124 were mirrorimages of first stage vanes 114, and were convex in the direction ofrotation. The vane curvature and/or other vane properties may, forexample, be used to disturb velocity fields locally.

In a number of embodiments, fiber bundle 200 was a generally cylindricalbundle of hollow fiber membranes (for example, siloxane and heparincoated fiber arrays, membranes or fabrics as described above) stacked inlayers at, for example, 5-15 degree angles to one another and alignedgenerally perpendicular to the principal direction of blood flow (thatis, generally perpendicular to axis A of housing 20 or generallyparallel to the plane of rotation (or radius) of impeller 100)—see FIGS.2A and 3C) to maximize gas exchange. In a number of representativestudied embodiments, fiber bundle 200 was a generally cylindrical bundleof hollow fiber membranes stacked in layers at approximately 7 degreeangles to one another. The ends of the hollow fibers were potted intosemi-circular gas manifolds (gas inlet manifold 160 and gas outletmanifold 170) located at the sides of system 10 in the orientation of,for example, FIG. 3B into which the fibers of fiber bundle opened.

Aligning the hollow fibers generally perpendicular (for example, withinnor more 5 degrees from perpendicular or within nor more than 2.5degrees of perpendicular) to axis A can significantly decrease volume(that is, improve compactness) as compared to systems in which hollowfibers are generally parallel to the axis of the housing. In suchsystems, an annular fiber bundle may be used, and a rotating element maybe placed in the central annular opening. In the configurationsdescribed herein, impeller 100 or other movable/rotatable element can beplaced very close to fiber bundle 200 and fiber bundle 200 can be maderelatively thin to achieve/increase active mixing throughout thethickness or axial depth fiber bundle 200. Active mixing is, forexample, limited to certain depth within the fiber bundle depending, forexample, upon the nature of impeller and impeller rotational speed(which may be optimized). As described further below, multiple,relatively thin fiber bundles (with, for example, interveningrotating/moveable elements to effect active mixing) may be used in thesystems hereof Controlling, for example, fiber bundle properties(including, for example, axial depth or thickness, porosity,permeability etc.) and impeller properties (including, for example,physical properties, positional placement, quantity etc.) to provide fora predetermined or optimized amount of active mixing throughout thedepth of one or more fiber bundles can be used to optimize efficiencyand minimize, for example, volume of the lung compartment and/or bloodtrauma. Moreover, in the case of hollow fibers oriented generallyperpendicular to axis A (or generally parallel to the plane of rotationof impeller 100), a relatively large impeller may be used to, forexample, minimize bundle thickness and increase active mixing. Asdescribed herein, impeller 100 may, for example, have a diameterapproximately equal to fiber bundle 200.

In a number of embodiments, fiber bundle 200 was sealed to axiallyextending sealing sections 46 formed on an inner wall of intermediatesection 40 to form the generally semi-circular manifolds. Sealingsections 46 may, for example, extend radially inward to contact and forma sealing connection with fiber bundle 200. Two sealing section 46 wereused to form generally semi-circular (that is, extending approximately180 degrees) manifolds. Additional sealing sections may, for example, beused to create manifolds that extend around the inner circumference ofhousing 10 less than 180 degrees.

Fiber bundle 200 may, for example, be wound and positioned within afour-piece reusable mold made from, for example, acetal (Delrin) forpotting. During potting, two-part polyurethane adhesive (available fromCas Chem, of Bayonne, N.J.) is injected into the mold. The mold is thencentrifuged to assure even distribution around the periphery without anyvoids. Once the adhesive has cured, the potted fibers are removed andtrimmed. This procedure establishes a common gas pathway between allfibers.

During operation, an oxygen-containing “sweep gas” (for example, oxygen)flows into gas inlet manifold 160 via gas flow inlet 42 and isdistributed through the lumens of the individual fiber membranes offiber bundle 200. Oxygen (O₂) diffuses out of the fibers into theflowing blood as carbon dioxide (CO₂) diffuses from blood into thefibers and is carried by the sweep gas to outlet manifold 170 andtherethrough to gas flow outlet 44. As described above, the blood thenleaves system 10 via blood flow outlet 52. Oxygen and carbon dioxideexit the lumens of the fibers into gas outlet manifold 170. As, forexample, illustrated in FIG. 3B, an inner diameter or flange 31 of firstend section 30 and an inner diameter of flange 51 of second end section50 (see, FIG. 3B) are smaller than the inner diameter of intermediatesection 40 to entrap fiber bundle 200 and form gas inlet manifold 160and gas outlet manifold 170. In the illustrated embodiment, a lower end(in the illustrated orientation of FIG. 3B) or flange of first endsection 30 contacts and forms a seal with an upper surface of fiberbundle 200. An upper end of flange or second end section 50 contacts andforms a seal with a lower surface of fiber bundle 200. Blood is therebyprevented from directly flowing into gas inlet manifold 160 and/or gasoutlet manifold 170. The potting of fiber bundle 200 prevents blood flowflowing radially out of fiber bundle 200 and into gas inlet manifold 160and/or gas outlet manifold 170.

Systems 10 used in studies hereof were not optimized. As furtherdescribed below, optimization may be effected, for example, using anumber of tools including CFD, bench testing and/or in vivo studies.FIG. 5 illustrates the experimental setup used in the studies hereofFIG. 6 illustrates pump-flow curves for system 10 over a range ofoperating speeds in a blood analogue fluid with viscosity of 3.5 cP.Operating between 2000-3000 RPM, system 10 could deliver flows from2-3.5 liters per minute or LPM while generating pressure heads from200-500 mmHg. This dynamic range enables system 10 to be attached usingperipheral and/or central placement modes using either access cannula ordirectly connecting grafts.

The O₂ and CO₂ exchange rates were also measured as a function of flowrate for system 10 using well established in-vitro protocols, andresults are illustrated in FIG. 7. In a representative operating rangeof interest of, for example, 2-3.5 LPM, CO₂ removal was significant(that is, from 150 ml/min to over 200 ml/min, which is very close to thefull metabolic requirements for CO₂ elimination). In practice, the CO₂removal rate can be adjusted downward by either reducing sweep gas flowthrough system 10 or by adding some CO₂ to the O₂ sweep gas. In theflowrate range described above, the O₂ exchange varied from 80 to 140ml/min, which may be increased via optimization. For example, CFDanalysis indicates that certain design changes may boost O₂ exchange.For example, one may optimize active mixing within system 10 by, forexample, making impeller shape changes or by adding an additionalrotating surface. A second impeller or moving/rotating/spinning elementor surface may, for example, be added at the bottom of fiber bundle 200to increase gas exchange efficiency. In other embodiments (asillustrated, for example, in FIG. 3D), a plurality of fiber bundles maybe used with impellers or moving/rotating/spinning surface at the endsof the plurality of fiber bundles and between the individual fiberbundles. In the embodiment of FIG. 3D, system 10 includes a first fiberbundle 200 a and a second fiber bundle 200 b. A rotating element 250 inthe form of a disk may, for example, be placed between fiber bundle 200a and second fiber bundle 200 b. Another rotating element 260 may, forexample, be placed adjacent (below in the illustrated orientation)second fiber bundle 200 b. Intermediate rotating element 250 may, forexample, include holes or passages 154 therethrough which may berelatively large to, for example, allow net blood flow from one bundleinto the next fiber bundle, while still imparting further velocityfields via the rotation of element 250. Second rotating element 260 maylikewise include holes or passages. Either or both of first rotatingelement 250 and second rotating element 260 may, for example, beprovided with vanes or other extending axially extending elements toenhance velocity fields created thereby. Additional fiber bundles androtating element may be provided in a generally serial arrangement alongthe axis of the system. One may improve the flow distribution into thefiber bundle(s) by, for example, optimizing the second stage of thetwo-stage impeller pump 100 of system 10 and/or other moving/rotatingelements thereof.

In a number of embodiments, passages or holes may be formed through theimpeller or other rotating element that is used to create a pressuredifferential (for example, impeller 100 or impeller 100 a). Althoughsuch holes or passages create inefficiency in pumping by creatingleakage, the associated leakage recirculation may decrease the risk ofclotting and increase active mixing. The pressure loss associated withrecirculation leakage may be offset by increasing the rate of spin ofthe impeller, which will enhance recirculation and active mixing. Suchsystems may be readily optimized to, for example, maximize activemixing/efficiency and/or minimize the likelihood of bloodtrauma/clotting.

In the in-vitro gas exchange tests, hemolysis data was obtained bymeasuring plasma free hemoglobin (pfHb) before (labeled 1) and after(labeled 2) the 8 hour gas exchange test as illustrated in FIG. 8. Whilethe increase in pfHb was modest. The tests underlying the data of FIG. 8were run over a range of flowrates and operating speeds with some shortperiods of low flow while inlet blood gas conditions were beingadjusted.

In some embodiments, zwitterionic-based hemocompatible coatings mayreplace the heparin coating currently used on siloxane plasma resistanthollow fiber membranes. Hemocompatible coating development may, forexample, be guided by gas permeance measurements on coated fibers andin-vitro comparative hemocompatibility tests.

As described above, computational fluid dynamics (CFD) may be used tooptimize the design and operational parameters of system 10 to meetrequirements for blood pumping, gas exchange, priming volume, and formfactor. CFD may be used to simulate blood flow and gas exchange. Uponvalidation, CFD may be incorporated into design optimization algorithms.

In that regard, CFD is an effective tool to streamline the designprocess of, for example, blood pumps and oxygenators. Developed andvalidated CFD simulations may be combined with formal designoptimization to analyze and refine the design of system 10 and bloodcontacting components thereof (including, for example, the impellerregion, other rotational surfaces, the fiber bundle, and connectingconduits). Optimization objectives may, for example, include maximizinggas exchange and minimizing the size of system 10. The objectives mayhave constraints imposed to ensure sufficient pumping capacity, whileminimizing trauma to blood. Optimization provides an optimal set ofdesign features such as impeller size and configuration, fiber bundlelayout, active mixing surfaces and blood inlet and outlet ports.

CFD simulation may, for example, include a number of approaches. Thelaminar Navier-Stokes equations may, for example, be solved usingcommercial codes such as Fluent (v14, ANSYS Inc., Canonsburg, Pa.) andLoci-Stream (v1.6.1, Streamline Numerics, Gainesville, Fla.). Turbulencemodeling in the rotor cavity region of the device may be applied asneeded in regions of sufficient Reynolds number or in the event of adisparity between CFD predictions and flow visualization results. Thefiber bundle may be modeled as a single lumped continuum (porous medium)using a modified Ergun equation to characterize the pressure losses andsuperficial velocity field therein. Oxygen and carbon dioxide exchangemay, for example, be modeled using a convection-diffusion-source masstransfer approach of along with a nonlinear O₂ gas transfer model and anonlinear CO₂ model. We developed a CFD model of complex blood flow andgas exchange in hollow fiber bundles which was experimentally validated.The CFD model is suitable to predict subtle features ofimpeller-generated flow patterns and the overall gas exchange.

Preliminary CFD analysis of blood flow has been performed for system 10,and the CFD predictions were generally consistent with experimentaldata. The impeller design produces sufficient pressure head to pumpfluid through the fiber bundle with excess pressure to provide bloodpumping capacity. A simulated velocity field illustrated in FIG. 9clearly shows the direct penetration of disturbed flow from impeller 100into the fiber bundle. This direct interaction of the impeller fieldwith the fiber bundle produces active mixing as discussed above, whichenhances gas exchange. A “disturbed” flow index (DFI) (defined as thefractional increase in the magnitude of velocity compared to that whichwould occur by passive flow at the same flowrate through system 10without impeller rotation) was computed. In FIG. 10, regions 1 or blueregions (DFI=1) indicate little disturbance proceeding to a regions 2 orgreen regions (DFI=50) and regions 3 or red regions (DFI=100). In theembodiment studied, the disturbed flow propagates about ⅓ or ½ thedistance into fiber bundle 100, which is demarcated between the dashedlines of FIG. 10. The fiber bundle in the studied embodiments wasapproximately is 0.88 inches in depth (0.0224 meter) and include 62layers of fiber fabric as described above. The disturbed flow (activemixing) the propagated approximately, 0.29 to 0.44 inches (orapproximately 0.0074 to 0.0112 meters). The studied embodiments werenot, however, optimized for depth of active mixing. FIG. 10 suggests,for example, that a rotating secondary impeller or surface below fiberbundle 200 may further disturb the flow field within the bundle.

One may computationally also assess the hemocompatibility of system 10using blood damage models for hemolysis, platelet activation, andthrombogenicity. A number of such models have been developedspecifically for implementation with CFD.

As described above, a formal gradient-based design optimization may beapplied to system 10. Such a formal approach differs from most so-calledCFD “design optimization” procedures found in the literature, which aresimply numerical variations of “trial and error.” Design features suchas rotor blade profile, blade angles, and fiber bundle dimensions can bemathematically parameterized and modified automatically by a numericalgradient-based optimization scheme to maximize gas exchange efficiencywhile simultaneously enhancing hemocompatibility as defined by numericalblood damage metrics. Discrete sensitivity analysis in the Loci-StreamCFD software may be implemented to provide highly-accurate sensitivitygradients of the objective function and constraints with respect to thedesign parameters. The NASA-funded Discrete software (Optimal LLC,Starkville, Miss.) may, for example, be used to effect shape changes tosystem 10.

Because of rather complex and coupled blood and gas flow paths, repeatednumerical analyses of the complete unit can be prohibitive. Therefore,CFD optimization may be complemented with bench testing to (a) calibrateand validate the numerical analysis, and (b) evaluate the performanceover the complete range of operating conditions. Direct experimentalstudies, although more expensive than CFD analysis, more readily provideassessment of gas exchange and surface washing as it relates tothrombogenicity. Furthermore, bench testing may reduce the need foranimal studies in the design iteration process. Bench tests may, forexample, be performed using well-established standards to characterizepumping ability, gas exchange, potential for hemolysis, and thrombosis.Flow visualization studies may, for example, be used to confirm that theCFD analysis predicts important features of the flow at the inlet, inthe impeller region, and the outlet that may influence blood damage(shear “hot” spots) or propensity for thrombosis (stagnant loci).

To evaluate the pumping ability of system 10, one may generatepressure-flow curves over a range of possible rotation rates in arecirculating loop containing only a reservoir and system 10. Pressurehead for system 10 may, for example, be measured using a differentialtransducer (Omega Engineering Inc., Stamford, Conn.) across the inletand outlet. A Hoffman clamp downstream from system 10 may, for example,be used to vary the flowrate and outlet pressure at specific rotationrates. Such experiments may, for example, be conducted using a bloodanalogue fluid (carboxymethylcellulose in water) with a viscositymatching the asymptotic viscosity of normal blood (3.5 cP).

As describe above, zwitterionic molecular coatings may be used toimprove hemocompatibility of system 10. For example, hemocompatiblezwitterionic phosphorylcholine (PC) or sulfobetaine (SB) molecules maybe bonded in place of heparin. A primary barrier to long-termrespiratory support with artificial lungs is the hemocompatibility issueassociated with the large membrane surface in contact with blood and theconcomitant need for systemic anticoagulation, which can lead tobleeding complications. Zwitterionic phosphorylcholine (PC) orsulfobetaine (SB) groups provide bioinert properties that reduce proteinadsorption and denaturation and have shown promisinganti-thrombogenicity and anti-fouling properties on other cardiovasculardevices and biosensors.

Zwitterionic based coatings (PC and SB) may, for example, be applied toaminated siloxane hollow fiber membranes for use in system 10. Gaspermeance measurements on fibers modified with zwitterionic basedcoatings may be used to ensure that fiber permeance to O₂ and CO₂ remainsufficiently high to have a negligible impact on gas exchangeperformance. In-vitro hemocompatibility assays may be performed oncandidate PC and SB coatings, along with the current siloxane-heparincoated fiber as a comparative control.

The base fiber membrane may, for example, be an aminated siloxane coatedhollow fiber membrane in fabric form obtained from Alung Technologies.This fiber fabric is the same fiber fabric used to create the heparincoated fiber discussed above, but is used prior to heparinizationprocess. Carboxyl end-group functional PC or SB macromolecules (short tolong chain of PC or SB groups) may be prepared via a thiol-ene radicalpolymerization technique. The thiol-ene radical polymerization techniqueoffers a powerful method to prepare the functional macromolecules in asimple process. The chain length of PC or SB moieties of themacromolecules can be manipulated by altering the initial monomerfeeding ratio and the preparation conditions. Using the generatedmacromolecules for surface modification is attractive from a costperspective and avoids concerns with the release of adsorbed highmolecular weight PC or SB bearing polymers.

The carboxyl end-group functionalized PC or SB macromolecules may, forexample, be covalently immobilized on the aminated hollow fiber surfacesby a condensation reaction between the carboxyl groups and surface aminogroups. This may, for example, be done by placing the fiber fabricwithin tubes with the synthesized mPC—COOH or mSB—COOH aqueous solution,adding condensation catalyst, 1-ethyl 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N-hydroxysuccinimidyl (NHS), andcontinuously mixing at 37° C. for 24 hrs to allow amide bond formationbetween the amino groups and carboxyl groups. The modification densityand effectiveness may be assessed depending on the functionalmacromolecules, chain length of the molecules and the reactivity(density) of the amino groups on the aminated hollow fibers. The surfacecomposition and the grafting density on the modified hollow fiber may beanalyzed by X-ray photoelectron spectroscopy (XPS).

We have demonstrated that we can successfully modify the aminatedsiloxane fiber (S-A) with PC (S-A-PC) and SB (S-A-SB) macromolecules,and that the modified fibers showed significantly reduced plateletdeposition compared to the uncoated control fiber (see FIG. 11).

The modification density varies depending on the functionalmacromolecular chain length and the reactivity (density) of amino groupson the aminated hollow fibers. Further amination treatments using radiofrequency glow discharge (RFGD) may be used to introduce furtherreactive amino groups on the hollow fibers. Conventional free radicalpolymerization as well as controlled/living radical polymerization suchas reversible fragmentation chain-transfer (RAFT) polymerization oratom-transfer radical polymerization (ATRP) may be used. Themodification techniques may be varied depending on the surfaces and thedemands of the modification efficiency. For example, conventional freeradical polymerization may be better for simple preparation andmodification of high molecular weight of PC or SB based polymers, andother controlled/living radical polymerization techniques may be betterfor the preparation of controlled carboxyl functional polymers orgeneration of controlled polymer brush layer on the hollow fibersurfaces. Further surface modification techniques may be used. Cellular(endothelial) coatings have, for example, also shown promise.

In measuring gas permeance of modified fibers, coated fibers may bemounted in a gas-gas permeance module (one fiber/module) with one endoccluded and the other connected (epoxied) to a gas flow pathway. In anumber of studies, a total of six modules are, for example, prepared andtested for type coated fiber. CO₂ or O₂ is introduced into each modulevia an applied pressure and the rate of gas diffusion through the fiberwall may be measured using a bubble flow meter connected to the outletgas pathways from all modules. Permeance (in) may be calculated by therate of gas flow divided by differential pressure and the exposed fibersurface area to gas. Permeance measurements may be made at both 23° C.and 37° C. As the coatings are molecular based, it is not expected thatgas permeance of coated fibers will be reduced compared to thesiloxane-heparin control. For application in system 10, CO₂ and O₂permeances above 1×10-4 and 1×10-5 ml/s/cm2/cmHg, respectively, will betargeted to ensure minimal effects of the coatings on gas.Siloxane-heparin fibers meets those targets.

In bench studies of platelet adhesion, platelet activation and thrombusformation, whole ovine blood may, for example, be collected by jugularvenipuncture. Hollow fiber samples with equivalent surface areas may beplaced in Vacutainer® tubes filled with the heparinized blood andincubated at 37° C. on a hematology mixer. After contact with the ovineblood, the surfaces may be rinsed and fixed in glutaraldehyde andprepared for scanning electron microscopy (SEM) to observe the plateletadhesion and the morphologies. The number of platelets deposited onhollow fiber samples may be determined by a lactate dehydrogenase (LDH)assay. The percentage of activated platelets in the bulk phase of theblood contacting the hollow fiber samples may be quantified with flowcytometric assay using annexin V protein or an antihuman CD62P antibody.

In-vivo animal studies may also be used to study the performance ofsystem 10 when connected to a circulatory system similar to humans andto establish correlations between functional performance in benchtesting and animal testing. These studies may be used for delineatingthe physiological and hemocompatibility impact of system 10 in amammalian model. Studies may, for example, be performed in healthysheep, as is standard practice in device development programs for bloodpumps and artificial lungs.

The foregoing description and accompanying drawings set forth a numberof representative embodiments at the present time. Variousmodifications, additions and alternative designs will, of course, becomeapparent to those skilled in the art in light of the foregoing teachingswithout departing from the scope hereof, which is indicated by thefollowing claims rather than by the foregoing description. All changesand variations that fall within the meaning and range of equivalency ofthe claims are to be embraced within their scope.

What is claimed is:
 1. An extracorporeal system for lung assistcomprising: a housing, a blood flow inlet in fluid connection with thehousing; a blood flow outlet in fluid connection with the housing; aplurality of hollow gas permeable fibers adapted to permit diffusion ofgas between blood and an interior of the hollow gas permeable fibers,the plurality of hollow gas permeable fibers being formed into a firstgenerally cylindrical bundle and being positioned between the blood flowinlet and the blood flow outlet such that blood flows around theplurality of hollow gas permeable fibers when flowing from the bloodflow inlet to the blood flow outlet, the plurality of hollow gaspermeable fibers extending generally perpendicular to an axis of thefirst generally cylindrical bundle and to the direction of bulk flow ofblood axially through the generally cylindrical bundle and through thehousing; a gas inlet in fluid connection with the housing and in fluidconnection with inlets of the plurality of hollow gas permeable fibers;a gas outlet in fluid connection with the housing and in fluidconnection with outlets of the plurality of hollow gas permeable fibers;and at least one moving element located outside the generallycylindrical bundle to create velocity fields in blood flow contactingthe plurality of hollow gas permeable fibers, wherein the moving elementis axially spaced from and directly adjacent an end of the firstgenerally cylindrical bundle via which blood enters the first generallycylindrical bundle and a surface of the moving element is no more than 1cm from the end of the first generally cylindrical bundle via whichblood enters the first generally cylindrical bundle, the at least onemoving element rotating in a plane generally perpendicular to the axisof the first generally cylindrical bundle.
 2. The system of claim 1wherein the system is a paracorporeal system.
 3. The system of claim 2wherein the at least one moving element comprises a rotating impelleradapted to pump blood from the blood flow inlet to the blood flowoutlet, the rotating impeller causing active mixing within the pluralityof hollow gas permeable fibers.
 4. The system of claim 3 wherein asurface of the rotating impeller is no more than 2 mm from the pluralityof hollow gas permeable fibers.
 5. The system of claim 4 wherein theimpeller has a diameter that is generally the same as a diameter of thefirst generally cylindrical bundle.
 6. The system of claim 5 wherein thefirst generally cylindrical bundle is formed from a plurality of layersof fiber fabric, each of the plurality of layers of fiber fabriccomprising hollow gas permeable fibers, wherein adjacent layers of fiberfabric are rotated relative to each other such that the orientation ofthe plurality of hollow gas permeable fibers in adjacent layers of fiberfabric are of a different orientation.
 7. The system of claim 6 whereina first seal is formed between the first generally cylindrical bundleand the housing at a first position and a second seal is formed betweenthe first generally cylindrical bundle and the housing at a secondposition, rotated around the circumference of the first generallycylindrical bundle from the first position, to form a gas inlet manifoldin fluid connection with the gas inlet on a first side of the first sealand the second seal and a gas outlet manifold in fluid connection withthe gas outlet on a second side of the first seal and the second seal,the first seal and the second seal blocking fluid connection between thegas inlet manifold and the gas outlet manifold.
 8. The system of claim 3wherein the impeller comprises a radially extending disk, a firstplurality of vanes extending axially from the disk on a first side ofthe disk and a second set of vanes extending axially from the disk on asecond side of the disk, the second side of the disk being opposite thefirst side.
 9. The system of claim 4 wherein the impeller comprises aplurality of magnets in operative connection therewith and the systemfurther comprises a magnetic drive system.
 10. The system of claim 9including a system to offset hydrodynamic force and magnetic couplingforce between the plurality of magnets and the magnetic drive.
 11. Thesystem of claim 10 wherein the system to offset hydrodynamic force andmagnetic coupling force between the plurality of magnets and themagnetic drive comprises a first magnet in operative connection with theimpeller which cooperates with a second magnet to create a repellantforce therebetween.
 12. The system of claim 3 further comprising arotating element positioned within the housing adjacent to the pluralityof hollow gas permeable fibers on an opposite side thereof of theimpeller, the rotating element rotating in a plane generallyperpendicular to the axis of the first generally cylindrical fiberbundle.
 13. The system of claim 12 wherein the rotating element is asecond impeller.
 14. The system of claim 3 wherein the impellercomprises one or more passages therethrough to result is recirculationassociated with leakage through the one or more passages.
 15. The systemof claim 2 wherein the plurality of hollow gas permeable fiberscomprises a plurality of layers of fiber fabric, each of the pluralityof layers of fiber fabric comprising hollow gas permeable fibers,wherein adjacent layers of fiber fabric are rotated relative to eachother such that the orientation of the plurality of hollow gas permeablefibers in adjacent layers of fiber fabric are of a differentorientation.
 16. The system of claim 2 wherein blood is blocked fromflowing to the gas inlet and the gas outlet.
 17. The system of claim 2wherein the plurality of hollow gas permeable fibers comprises at leastone zwitterionic species tethered on surfaces thereof or heparintethered on surfaces thereof.
 18. The system of claim 2 including asystem to offset hydrodynamic force.
 19. The system of claim 18 whereinthe system to offset hydrodynamic force comprises a first magnet inoperative connection with the impeller which cooperates with a secondmagnet to create a repellant force therebetween.
 20. The system of claim2 wherein the system is adapted to adjustably deliver flows in the rangeof approximately 2 to 4 liters per minute.
 21. The system of claim 2further comprising a first pivot bearing on a first side of the moveableelement and a second pivot bearing on a second side of the moveableelement.
 22. The system of claim 2 further comprising: at least a secondplurality of hollow gas permeable fibers spaced from the plurality ofhollow gas fibers, the second plurality of hollow gas permeable fibersbeing adapted to permit diffusion of gas between blood and an interiorof the second plurality of hollow gas permeable fibers, the secondplurality of hollow gas permeable fibers being formed into a secondgenerally cylindrical bundle and being spaced from the plurality ofhollow gas permeable fibers between the blood flow inlet and the bloodflow outlet such that blood flows around the second plurality of hollowgas permeable fibers when flowing from the blood flow inlet to the bloodflow outlet, the second plurality of hollow gas permeable fibersextending generally perpendicular to an axis of the second generallycylindrical bundle and to the direction of bulk flow of blood throughthe housing; the gas inlet being in fluid connection with inlets of thesecond plurality of hollow gas permeable fibers, wherein the gas outletis in fluid connection with outlets of the second plurality of hollowgas permeable fibers, the axis of the second generally cylindricalbundle being generally collinear with the axis of the first generallycylindrical bundle.
 23. The system of claim 22 further comprising atleast a second moving element located outside the second generallycylindrical bundle to create velocity fields in blood flow contactingthe second plurality of hollow gas permeable fibers positioned betweenthe plurality of hollow gas permeable fibers and the second plurality ofhollow gas permeable fibers to be axially spaced from an end of thesecond generally cylindrical bundle, the second moving element rotatingin a plane generally perpendicular to the axis of the second generallycylindrical bundle.
 24. A method for extracorporeal lung assistcomprising: providing a plurality of hollow gas permeable fibers withina housing, the plurality of hollow gas permeable fibers being adapted topermit diffusion of gas between blood and an interior of the hollow gaspermeable fibers, the plurality of hollow gas permeable fibers beingformed into a generally cylindrical bundle and being positioned betweena blood flow inlet and a blood flow outlet such that blood flows aroundthe plurality of hollow gas permeable fibers when flowing from the bloodflow inlet to the blood flow outlet, the plurality of hollow gaspermeable fibers extending generally perpendicular to an axis of thegenerally cylindrical bundle and to the direction of bulk flow of bloodaxially through the generally cylindrical bundle and through thehousing; flowing a sweep gas including oxygen through the plurality ofhollow gas permeable fibers; and moving at least one movable elementlocated outside the generally cylindrical bundle, a surface of the atleast one moveable element being positioned to be axially spaced no morethan 1 cm from an end of the generally cylindrical bundle via whichblood enters the generally cylindrical bundle, the at least one movableelement rotating in a plane generally perpendicular to the axis of thegenerally cylindrical bundle to create velocity fields in blood flowcontacting the plurality of hollow gas permeable fibers.